Institut de Biologie StructuraleGrenoble / France

Targeting host proteins to fight influenza

New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, researchers from the IBS/VRM group, in collaboration with the Institut Pasteur, University Paris Diderot and University Paris Descartes, focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. They identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. They solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. They show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, their data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.

Destabilization of the human RED–SMU1 splicing complex as a basis for host-directed antiinfluenza strategy. Ashraf U, Tengo L, Le Corre L, Fournier G, Busca P, McCarthy AA, Rameix-Welti M-A, Gravier-Pelletiere C, Ruigrok RW, Jacob Y, Vidalain P-O, Pietrancosta N, Crépin T, Naffakh N. Proc Natl Acad Sci USA ;116(22):10968-10977.